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Small changes in the mitochondrial DNA (mtDNA) can lead to severe effects over time. Recently, we have shown that minor base changes in the mtDNA of conplastic mouse strains in the C57Bl/6 genomic background may affect hallmarks of AD (Scheffler et al., 2012). Alterations in ATP-production caused by mtDNA changes resulted in direct suppression of beta-amyloid clearance from the brain by ATP-depending exporters (ABC transporters). Microglial function was also compromised.
Researchers continue to debate the role maternal inheritance in the pathogenesis of sporadic AD. Consistently, even small mitochondrial genomic abberations may show long-term effects that converge in aging and neurodegeneration.

These are exciting findings that make important contributions to an ever growing body of science indicating that perturbation in mitochondrial function is an early and antecedent event in the pathogenesis of neurodegenerative diseases such as Alzheimer’s. These latest findings are consistent with our previous report that mitochondrial / bioenergetic deficits precede appearance of AD pathology in female mouse models of Alzheimer’s disease. It was surprising to us that the bioenergetic deficit was evident even in embryonic neurons derived from the same mouse model (Yao et al., 2009). Analyses in humans by Mosconi and Swerdlow are consistent with these preclinical studies where they found reduced mitochondrial cytochrome c oxidase activity in platelets and reduced brain glucose metabolism in adult children with maternal history of Alzheimer’s disease (Mostoni et al., 2010; Mosconi et al., 2011).

Collectively a growing body of data from preclinical to clinical indicate that deficits in mitochondrial function are likely a risk factor for late-onset Alzheimer’s disease. These findings also indicate the therapeutic potential of targeting mitochondria for disease prevention.